Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides

Abstract

Substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides, their N-oxide forms, their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms having gastrointestinal motility stimulating properties, compositions containing the same, and methods of treating warm-blooded animals suffering from motility disorders of the gastrointestinal system.

We claim: 
     
       1. A compound of the formula: ##STR65## an N-oxide form, a pharmaceutically acceptable acid addition salt, or a stereoisomeric form thereof, wherein: R 1  represents hydrogen, C 1-6  alkyl, arylC 1-6  alkyl, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, aryloxycarbonyl, aminoC 1-6  alkyl, mono- or di(C 1-6  alkyl)aminoC 1-6  alkyl, aminocarbonyl, mono- or di(C 1-6  alkyl)aminocarbonyl, pyrrolidinylcarbonyl, or piperidinylcarbonyl;   wherein aryl represents phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-6  alkyl, C 1-6  alkyloxy, aminosulfonyl, C 1-6  alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarbonyl, and phenylcarbonyl;   R 2  represents hydrogen or C 1-6  alkyl;   R 3 , R 4 , and R 5  each independently represent hydrogen, C 1-6  alkyl, C 1-6  alkyloxy, halo, hydroxy, cyano, nitro, amino, trifluoromethyl, mono- or di(C 1-6  alkyl)amino, aminocarbonyl, arylcarbonylamino, C 1-6  alkylcarbonylamino, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonyloxy, aminosulfonyl, C 1-6  alkylaminosulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, mercapto, arylC 1-6  alkyloxy, or aryloxy, wherein aryl is as defined above;   R 6  represents hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkyloxy, halo, or amino; and   L represents a radical of the formula: ##STR66##  wherein: Y represents O, S, NR 7 , or a direct bond, wherein R 7  represents hydrogen or C 1-6  alkyl;   R 15  and R 16  each independently represent hydrogen, C 1-6  alkyl, hydroxy, C 1-6  alkyloxy, amino, mono- or di(C 1-6  alkyl)amino, hydroxyC 1-6  alkyl, C 1-6  alkylcarbonyl, C 1-6  alkyloxycarbonyl, aminocarbonyl, mono- or di(C 1-6  alkyl)-aminocarbonyl, or 2-C 1-6  alkyl-1,3-dioxolan-2-yl, or R 15  and R 16  combined with the carbon atom bearing said R 15  and R 16  may form a carbonyl or a 1,3-dioxolan-2-ylidene radical;   s represents 1, 2, or 3;   A represents O, S, or NR 19 , wherein said R 19  represents hydrogen, C 1-6  alkyl, aryl, pyridinyl, pyrimidinyl, C 1-6  alkylcarbonyl, C 1-6  alkyloxycarbonyl, or arylC 1-6  alkyl, wherein aryl is as defined above;   R 17  and R 18  each independently represent hydrogen or C 1-6  alkyl, or when A represents NR 19 , R 17  and R 18  taken together may form a fused benzene residue being optionally substituted with halo or C 1-6  alkyl;   t represents the integer 1 or 2;   R 20  represents hydrogen or C 1-6  alkyl;   B represents a bivalent radical of the formula --CH 2  --CH 2  --, -C(═O)--CH 2  --, or --CH 2  --CH 2  --CH 2  --, wherein each hydrogen atom independently may be replaced by C 1-6  alkyl substituents, or when R 20  represents C 1-6  alkyl, said bivalent radical may also be 1,2-benzenediyl optionally substituted with halo or C 1-6  alkyl;   E represents a bivalent radical of the formula --CH 2  --CH 2  --, --CH 2  --N(R 21 )--, or --CH 2  --CH 2  --CH 2  --, wherein each hydrogen atom independently may be replaced by C 1-6  alkyl, or said bivalent radical may also be 1,2-benzenediyl optionally substituted with halo or C 1-6  alkyl, wherein said R 21  represents hydrogen or C 1-6  alkyl;   R 22 , R 23 , and R 24  each independently represent hydrogen or C 1-6  alkyl;   n and m each independently represent 0 or 1; and   G represents carbonyl, carboxymethylene, C 1-6  alkyloxycarbonylmethylene, C 1-6  alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene or, 1,3-dioxolan-2ylidene.   
     
     
       2. A compound according to claim 1 wherein R 1  is hydrogen, C 1-6  alkyl, aryloxycarbonyl, mono- or di(C 1-6  alkyl)aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; R 2  is hydrogen; and R 3 , R 4  and R 5  each independently are hydrogen, halo, C 1-6  alkyloxy, amino, mono- or di(C 1-6  alkyl)amino, C 1-6  alkylcarbonylamino, nitro, aminosulfonyl, C 1-6  alkylaminosulfonyl or C 1-6  alkylsulfonyl. 
     
     
       3. A compound according to claim 2 wherein the substituents on the 3- and the 4position of the piperidine ring have the cis configuration. 
     
     
       4. A compound according to claim 3 wherein aryl represents phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-4  alkyl, and C 1-4  alkyloxy, Alk represents a C 1-4  alkanediyl group, and L represents a group of the formula: (f) wherein Y represents O, NR 7 , or a direct bond, R 15  represents hydrogen, C 1-4  alkyl, hydroxy, C 1-4  alkyloxy, amino, mono- or di(C 1-4  alkyl)amino, hydroxyC 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or aminocarbonyl, and R 16  represents hydrogen or C 1-4  alkyl, or R 15  and R 16  combined with the carbon atom bearing said R 15  and R 16  may form a carbonyl or a 1,3-dioxolan-2-ylidene radical; or   (g) wherein Y represents O, NR 7 , or a direct bond and A represents O or NR 19 , wherein R 19  represents hydrogen, C 1-6  alkyl, aryl, pyridinyl, pyrimidinyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or arylC 1-4  alkyl; or   (h) wherein B represents 1,2-ethanediyl or when R 20  represents C 1-4  alkyl B may also be 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl; or   (i) wherein E represents 1,3-propanediyl optionally substituted with C 1-4  alkyl, 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl, or a bivalent radical of the formula --CH 2  --N(R 21 )--, said R 21  being hydrogen or C 1-4  alkyl; or   (j) wherein R 23  and R 24  are both hydrogen; or   (k) wherein G represents carbonyl, C 1-4  alkyloxycarbonylmethylene, C 1-4  alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene, or 1,3-dioxolan-2-ylidene.   
     
     
       5. A compound according to claim 4 wherein the benzamide part is substituted on the meta position with R 3  being chloro, bromo, C 1-4  alkylaminosulfonyl, aminosulfonyl or C 1-4  alkylsulfonyl, on the para position with R 4  being amino and on the ortho position with R 5  being hydroxy or C 1-4  alkyloxy. 
     
     
       6. A compound according to claim 1 wherein L is a radical of formula (k). 
     
     
       7. A compound according to claim 1 wherein L is a radical of formula (f), (g), (h) or (i). 
     
     
       8. The compound of claim 1 wherein said compound is a cis-4-amino-5-chloro-2-methoxy-N[3-methoxy-1-alkyl-4-piperidinyl]-benzamide. 
     
     
       9. The compound of claim 8 wherein said compound is a member selected from the group consisting of: cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4-(1-pyrrolidinyl)butyl]-4piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[3-methyl-4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2-oxo-1-imidazolinyl)-ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(2-oxo-1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-methyl-4-(2-methyl-1-piperidinyl)-4-oxobutyl]-4-piperidinyl]benzamide; and   cis-4-amino-5-chloro-N-[1-[4-[4-(dimethylamino)-1-piperidinyl]-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.   
     
     
       10. A pharmaceutical composition comprising one or more inert carriers and as active ingredient a gastrointestinal motility stimulating amount of a compound as claimed in claim 1. 
     
     
       11. A pharmaceutical composition according to claim 10 wherein R 1  is hydrogen, C 1-6  alkyl, aryloxycarbonyl, mono- or di(C 1-6  alkyl)aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; R 2  is hydrogen; and R 3 , R 4  and R 5  each independently are hydrogen, halo, C 1-6  alkyloxy, amino, mono- or di(C 1-6  alkyl)amino, C 1-6  alkylcarbonylamino, nitro, aminosulfonyl, C 1-6  alkylaminosulfonyl or C 1-6  alkylsulfonyl. 
     
     
       12. A pharmaceutical composition according to claim 11 wherein the substituents on the 3- and the 4- position of the piperidine ring have the cis configuration. 
     
     
       13. A pharmaceutical composition according to claim 12 wherein aryl represents phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-4  alkyl, and C 1-4  alkyloxy, Alk represents a C 1-4  alkanediyl group, and L represents a group of the formula: (f) wherein Y represents O, NR 7 , or a direct bond, R 15  represents hydrogen, C 1-4  alkyl, hydroxy, C 1-4  alkyloxy, amino, mono- or di(C 1-4  alkyl)amino, hydroxyC 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or aminocarbonyl, and R 16  represents hydrogen or C 1-4  alkyl, or R 15  and R 16  combined with the carbon atom bearing said R 15  and R 16  may form a carbonyl or a 1,3-dioxolan-2-ylidene radical; or   (g) wherein Y represents O, NR 7 , or a direct bond and A represents O or NR 19 , wherein R 19  represents hydrogen, C 1-6  alkyl, aryl, pyridinyl, pyrimidinyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or arylC 1-4  alkyl; or   (h) wherein B represents 1,2-ethanediyl or when R 20  represents C 1-4  alkyl B may also be 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl; or   (i) wherein E represents 1,3-propanediyl optionally substituted with C 1-4  alkyl, 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl, or a bivalent radical of the formula --CH 2  --N(R 21 )--, said R 21  being hydrogen or C 1-4  alkyl; or   (j) wherein R 23  and R 24  are both hydrogen; or   (k) wherein G represents carbonyl, C 1-4  alkyloxycarbonylmethylene, C 1-4  alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene, or 1,3-dioxolan-2-ylidene.   
     
     
       14. A pharmaceutical composition according to claim 13 wherein the benzamide part is substituted on the meta position with R 3  being chloro, bromo, C 1-4  alkylaminosulfonyl, aminosulfonyl or C 1-4  alkylsulfonyl, on the para position with R 4  being amino and on the ortho position with R 5  being hydroxy or C 1-4  alkyloxy. 
     
     
       15. A pharmaceutical composition according to claim 10 wherein L is a radical of formula (f), (g), (h) or (i). 
     
     
       16. A method of treating warm-blooded animals suffering from motility disorders of the gastrointestinal system, which method comprises the systemic administration to said warm-blooded animals of an effective gastrointestinal stimulating amount of a compound as claimed in claim 1. 
     
     
       17. A method according to claim 16 wherein R 1  is hydrogen, C 1-6  alkyl, aryloxycarbonyl, mono- or di(C 1-6  alkyl)aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; R 2  is hydrogen; and R 3 , R 4  and R 5  each independently are hydrogen, halo, C 1-6  alkyloxy, amino, mono- or di(C 1-6  alkyl)amino, C 1-6  alkylcarbonylamino, nitro, aminosulfonyl, C 1-6  alkylaminosulfonyl or C 1-6  alkylsulfonyl. 
     
     
       18. A method according to claim 17 wherein the substituents on the 3- and the 4- position of the piperidine ring have the cis configuration. 
     
     
       19. A method according to claim 18 wherein aryl represents phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-4  alkyl, and C 1-4  alkyloxy, Alk represents a C 1-4  alkanediyl group, and L represents a group of the formula: (f) wherein Y represents O, NR 7 , or a direct bond, R 15  represents hydrogen, C 1-4  alkyl, hydroxy, C 1-4  alkyloxy, amino, mono- or di(C 1-4  alkyl)amino, hydroxyC 1-4  alkyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or aminocarbonyl, and R 16  represents hydrogen or C 1-4  alkyl, or R 15  and R 16  combined with the carbon atom bearing said R 15  and R 16  may form a carbonyl or a 1,3-dioxolan-2-ylidene radical; or   (g) wherein Y represents O, NR 7 , or a direct bond and A represents O or NR 19 , wherein R 19  represents hydrogen, C 1-6  alkyl, aryl, pyridinyl, pyrimidinyl, C 1-4  alkylcarbonyl, C 1-4  alkyloxycarbonyl, or arylC 1-4  alkyl; or   (h) wherein B represents 1,2-ethanediyl or when R 20  represents C 1-4  alkyl B may also be 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl; or   (i) wherein E represents 1,3-propanediyl optionally substituted with C 1-4  alkyl, 1,2-benzenediyl optionally substituted with halo or C 1-4  alkyl, or a bivalent radical of the formula --CH 2  --N(R 21 )--, said R 21  being hydrogen or C 1-4  alkyl; or   (j) wherein R 23  and R 24  are both hydrogen; or   (k) wherein G represents carbonyl, C 1-4  alkyloxycarbonylmethylene, C 1-4  alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene, or 1,3-dioxolan-2-ylidene.   
     
     
       20. A method according to claim 19 wherein the benzamide part is substituted on the meta position with R 3  being chloro, bromo, C 1-4  alkylaminosulfonyl, aminosulfonyl or C 1-4  alkylsulfonyl, on the para position with R 4  being amino and on the ortho position with R 5  being hydroxy or C 1-4  alkyloxy. 
     
     
       21. A method according to claim 16 wherein L is a radical of formula (f), (g), (h) or (i). 
     
     
       22. The pharmaceutical composition according to claim 10 wherein said compound is a cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-alkyl-4-piperidinyl]benzamide. 
     
     
       23. The pharmaceutical composition according to claim 22 wherein said compound is a member selected from the group consisting of: cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4-(1-pyrrolidinyl)butyl]-4piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[3-methyl-4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2oxo-1-imidazolinyl)-ethyl]-3-methoxy-4piperidinyl]-2-methoxybenzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(2-oxo-1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-methyl-4-(2-methyl-1-piperidinyl)-4-oxobutyl]-4-piperidinyl]benzamide; and   cis-4-amino-5-chloro-N-[1-[4-[4-(dimethylamino)-1-piperidinyl]-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.   
     
     
       24. The method according to claim 16 wherein said compound is a cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-alkyl-4-piperidinyl]benzamide. 
     
     
       25. The method according to claim 24 wherein said compound is a member selected from the group consisting of: cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-[3-methyl-4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2-oxo-1-imidazolinyl)-ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(2-oxo-1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;   cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-methyl-4-(2-methyl-1-piperidinyl)-4-oxobutyl]-4-piperidinyl]benzamide; and   cis-4-amino-5-chloro-N-[1-[4-[4-(dimethylamino)-1-piperidinyl]-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.